Full Title: The Impact of Lymph Node Station on Survival in 348 Patients with Surgically Resected Malignant Pleural Mesothelioma: Implications for Revision of the American Joint Committee on Cancer Staging System

The current system for staging cases of pleural mesothelioma is based on a TNM model, where the determination of disease stage is based on the relationship between tumor status (T stage), lymph node status (N stage) and the presence or absence of distant metastases (M stage). This system was proposed in 1995, validated through a number of reports and subsequently accepted as the standard mesothelioma staging system by the American Joint Committee on Cancer Staging System, as well as by the Union Internationale Contre le Cancer.

However, a number of questions regarding its underlying classification structure have existed since it was initially proposed. Writing in the journal The Journal of Thoracic and Cardiovascular Surgery, physicians from the Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City state that the current staging system was designed to be adjusted as more and better data regarding the classification of nodal status was developed. The authors of the article note that the staging system uses the lymph node map developed for lung cancer staging, but that pleural mesothelioma may require a different pattern map because lymphatic drainage from the pleura may differ from that of the lung.

To answer these questions, as well as others regarding the nodal classification system in mesothelioma patients, the physicians from MSKCC conducted a study on patients with pleural mesothelioma who were treated at their institution and they have recently published their results in an article entitled “The Impact of Lymph Node Station on Survival in 348 Patients with Surgically Resected Malignant Pleural Mesothelioma: Implications for Revision of the American Joint Committee on Cancer Staging System.”

Overview of the Study

The staging system is only applicable to surgical patients, so the retrospective study that the physicians conducted was limited to those patients who underwent either extrapleural pneumonectomy (EPP) or pleurectomy/decortication (P/D). 348 patients were finally selected for analysis. The sample population, as is common with all forms of mesothelioma, was heavily male gender with the epitheloid histological subtype. 222 patients received EPP, while 126 underwent P/D. Most patients were Stage III at time of surgery.

These patient records were analyzed on a number of fronts, including nodal status (both individual and concurrent metastases), common nodal station involvement, surgical procedures and time to survival.

Results

Overall median survival for the entire patient cohort was 15 months, with significant variations in survival when patients were analyzed for differences in nodal status, as well as histological subtype and overall stage. Patients with N0 or N1 status demonstrated a 19-month median survival time, while patients positive for N2, N2/N1 or internal thoracic node metastases demonstrated a 10-month median survival. Patients with only N2 status did not differ significantly from patients who were positive for both N2 and N1, but multiple N2 nodal stations were indicative of more restricted median survival time.

Other variations in survival were also reported: epitheloid vs. non-epitheloid histology, with non-epitheloid disease associated with worse survival; male gender vs. female gender, with men demonstrating a worse prognosis then women; Stage III/IV patients were associated with shorter survival than were Stage I/II patients.

Conclusion

In the discussion section of the article, the authors considered the importance of their findings in relation to the current staging system. Their results show that pleural mesothelioma is most likely to metastasize to N2 nodes, rather than to N1 nodes. The authors also note that because patients positive for only N1 nodes were associated with longer median survival than were patients positive any form of N2 metastases, the staging system should likely be changed to incorporate this distinction.

These results also confirmed an earlier study these physicians conducted which found that nodal metastasis is common in patients with pleural mesothelioma—nearly 50% of the patient cohort demonstrated some lymph node involvement.

Along with the differences in survival between N1 and N2 status, the results also demonstrated that metastases in multiple N2 nodal stations correlates with a worse prognosis than does N2 status in only one station. Because of this, the authors also state that the staging system could possibly be adjusted to show that multiple N2 stations reflect a higher stage than does a single N2 station.

The authors close the article with a call for larger study on the impact of nodal status on mesothelioma prognosis. Their research indicates grounds for revision of the staging system, but a larger, multicenter study would be needed to confirm these findings.

Malignant Mesothelioma is most commonly a disease of the older and the elderly. The vast majority of all mesothelioma diagnoses are for men and women (although, mainly men), older that 55 or 60. However, the disease can, albeit very rarely, affect teenagers and young adults. Because mesothelioma is so rarely seen in these populations, studies are impossible to perform and little is understood about the best treatment regimens or the prognostic indicators involved in determining overall treatability. The only way to share information about these cases is through the publication of individual case reports in medical journals.

Physicians from the Dana-Farber Cancer Institute and from Brigham & Women’s Hospital have recently published an article on their treatment of four pediatric peritoneal mesothelioma cases. The case reports describe how the physicians treated these patients and how each responded to these therapies. They close the article with a number of recommendations regarding the future treatment of pediatric mesothelioma cases.

Case Reports

The authors report on four cases of pediatric mesothelioma:

• A previously healthy 17-year-old female with a number of symptoms, including deep vein thrombosis of the left arm, a left-side pleural effusion and an unknown pelvic mass. Fluid in her peritoneum tested positive for mesothelioma.
• A previously healthy 16-year-old male with pelvic pain and weight loss, among other symptoms, had a biopsy of a diffuse tumor mass in his pelvis which revealed peritoneal mesothelioma.
• A previously healthy 20-year-old male with a Klebsiella pneumonia, pleural effusion and a mass in the tissue surrounding his kidneys tested positive for peritoneal mesothelioma.
• A 16-year-old female with a prior cancer history (neuroblastoma at 12) who had achieved complete remission, presented with abdominal pain that was discovered to be caused by peritoneal mesothelioma.

None of the patients had any personal risk factors for mesothelioma, and none were smokers. However, three of them had fathers who were likely exposed to asbestos during their work in construction. None of the men had any evidence of pleural mesothelioma or peritoneal mesothelioma, but we know that the disease can affect the children and spouses of exposed workers before they are diagnosed, or even if they are never diagnosed.

Treatment Regimen and Response

After the patients were diagnosed with peritoneal mesothelioma, they all received the same basic treatments as an adult would receive. All of the patients received systematic chemotherapy using pemetrexed and cisplatin; two of the patients received surgical debulking prior to their chemotherapy.

The median survival for the group was 40.3 months. At the time the article was published, three of the four were still alive. Two of these were progression free at 45 and 57 months, respectively, while the third demonstrated some progression at 22 months, but will still alive at 24 months.

Conclusion

The authors conclude their article by raising the question as to the relationship between asbestos exposure and the development of either pleural mesothelioma or peritoneal mesothelioma, especially in pediatric cases. They note that while the incidence of the pleural disease is to be expected based on the way in which these exposures occur, the reasons for the development of peritoneal mesothelioma are still unknown. They wonder if the precise nature of the exposures—whatever they may be, as the question remains totally open for these four patients—may explain the development of peritoneal disease in place of pleural disease.

They also conclude that, where applicable, pediatric cases should be treated in the same manner as adult cases are treated: they should receive debulking surgery if possible and intravenous systemic chemotherapy. The authors also believe that these patients should be eligible for enrollment in adult-focused clinical trials.

Eli Lilly has announced that its cancer drug Alimta, when used in combination with cisplatin, has received FDA approval for the first-line treatment of “locally-advanced and metastatic non-small cell lung cancer (NSCLC), for patients with nonsquamous histology.” The FDA’s new approval is the third overall approval that Alimta has received, and the second for its use in first-line therapy. The drug is most well known for the first-line treatment of pleural mesothelioma where it—again in combination with cisplatin—represents the chemotherapy standard of care for the treatment of the disease. It has also received approvals in single-agent use for the second-line treatment of NSCLC after prior chemotherapy treatment.